Areas of Interest

Research Interests

Rho family small G proteins in breast cancer

We focus on signaling pathways regulated by Rho GTPases that contribute to breast cancer initiation and progression. Rho GTPases are small GTP binding proteins that function as molecular switches to control various aspects of cell motility and proliferation, including actin cytoskeletal organization, cell cycle progression and mitosis. Current studies center on the role of the RhoA activating protein Net1 in breast cancer initiation and progression. Net1 is a unique RhoA regulatory protein that shuttles between the nucleus and plasma membrane and is overexpressed in a number of human cancers, including breast cancer. We have shown that Net1 is required for breast cancer cell motility and invasive activity, mitotic progression, and DNA damage responses in breast cancer cells, and for normal mammary gland development in the mouse. Ongoing projects in the lab include: a) defining molecular mechanisms by which Net1 proteins control breast cancer cell motility in vitro and metastasis in vivo; b) characterization of the role of Net1 in regulating mitotic progression and genomic stability; c) understanding how Net1 regulates the cellular response to DNA damage caused by therapeutics relevant to breast cancer, such as ionizing radiation and DNA damaging agents; d) elucidating the role of Net1 in mouse mammary gland development, tumorigenesis and metastasis.

A tutorial in my laboratory will provide a student with experience in molecular, biochemical, and cell biological techniques used in studying signaling in breast cancer cells in vitro and in mouse models of breast cancer.

Publications

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REFERENCES

  • Carr HS, Chang J, and Frost JA. (2021).  The PDZ domain protein SYNJ2BP regulates GRK-dependent Sst2A phosphorylation and downstream MAPK signaling. Endocrinology, 162(2):bqaa229. doi: 10.1210/endocr/bqaa229.
  • Sin T, Zhang G, Zhang Z, Zhu J, Yan Z, Frost JA, Li M, and Li YP. (2021). Cancer-induced muscle wasting requires p38beta MAPK activation of p300. Cancer Research, 81(4):885-897. doi: 10.1158/0008-5472.CAN-19-3219.
  • Wang P, van der Hoeven D, Ye N, Chen H, Liu Z, Ma X, Montufar-Solis D, Rehl KM, Cho K-J, Thapa S, Chen W, van der Hoeven R, Frost JA, Hancock JF, and Zhou J. (2021) Scaffold Repurposing of Fendiline: Identification of Potent KRAS Plasma Membrane Localization Inhibitors. Eur. J. Med. Chem., 217:113381. doi: 10.1016/j.ejmech.2021.113381.
  • Ulu A, Oh W, Zuo Y, Carr HS, and Frost JA. (2021).  Cdk1 phosphorylation negatively regulates the activity of Net1 towards RhoA during mitosis. Cell. Signal., 80:109926. doi: 10.1016/j.cellsig.2021.109926.
  • Li L, Li J, Zuo Y, Frost JA, and Yang Q. (2019). Opening KCNQ channels to prevent the development of paclitaxel-induced peripheral neuropathy. The Journal of Pain, 20(5):528-539. doi: 10.1016/j.jpain.2018.11.001.
  • Olsen C, Memarzadeh K, Ulu A, Carr HS, Bean AJ, and Frost JA. (2019) Regulation of Somatostatin receptor 2 trafficking by C-tail motifs and the retromer. Endocrinology, 160(5):1031-1043. doi: 10.1210/en.2018-00865.
  • Frost JA.  (2018).  Net1 (Neuroepithelial Cell Transforming Gene 1 Protein).  Encyclopedia of Signaling Molecules, 2nd Edition In: Choi S. (eds) Encyclopedia of Signaling Molecules.  Springer, Cham.
  • Rodriguez M, Frost JA, and Schonbrunn A.  (2018).  Real-time signaling assays demonstrate somatostatin agonist bias for ion channel regulation in somatotroph tumor cells.  J Endo Soc., 2(7):779-793. doi:10.1210/js.2018-00115.
  • Ulu A, and Frost JA.  (2018).  Regulation of RhoA Activation and Cell Motility by c-Jun N-terminal Kinases and Net 1.  Small GTPases. 1-7. doi: 10.1080/21541248.2018.1536638.
  • Ulu A, Oh W, Zuo Y, and Frost JA. (2018).  Regulation of subcellular localization of the RhoGEF Net1A by stress activated MAPKs and CRM1. J Cell Sci, 131(3), jcs204644. doi:10.1242/jcs.204644.
  • Zuo Y, Ulu A, Chang J, and Frost JA. (2018).  Contributions of the RhoA guanine nucleotide exchange factor Net1 to polyoma middle t antigen mediated mammary gland tumorigenesis and metastasis. Breast Cancer Res, 20(1):41. doi: 10.1186/s13058-018-0966-2.
  • Van der Hoeven D, Cho KJ, Zhou Y, Ma X, Chen W, Naji A, Kovar SE, Montufar-Solis D, Zuo Y, Frost JA, van der Hoeven RV, and Hancock JF. (2017).  Sphingomyelin metabolism is a regulator of KRAS function. Mol Cell Biol. Nov 20. pii: MCB.00373-17. doi: 10.1128/MCB.00373-17.
  • Wu Z, Li L, Xie F, Du J, Zuo Y, Frost JA, Carlton SM, Walters ET, and Yang Q. (2017).  Suppression of spontaneous activity in DRG neurons by activation of KCNQ channels reduces chronic pain after spinal cord injury. J Pain, Journal of Neurotrauma, 34(6):1260-1270.
  • Zuo Y, d’Aigle J, Chauhan A, and Frost JA. (2017).  Genetic deletion of the Rho GEF Net1 impairs macrophage motility and actin cytoskeletal organization. Small GTPases, Dec 31:1-8. doi: 10.1080/21541248.2017.1405772.
  • Ulu A, and Frost JA. (2016).  Regulation of RhoA activation and cytoskeletal organization by acetylation. Small GTPases, 7(2):76-81.
  • Zuo Y, Oh W, Ulu A and Frost JA. (2016).  Mouse models of Rho GTPase function in mammary gland development, tumorigenesis and metastasis. Mol Endo, 30(3):278-89.
  • Song EH, Carr HS, Zuo Y and Frost JA. (2015).  Acetylation dependent regulation of the subcellular localization and activity of the RhoGEF Net1A. J Cell Sci, 128(5):913-22.
  • Oh W, and Frost JA. (2014).  Rho GTPase independent regulation of ATM activation and cell survival by the RhoGEF Net1A. Cell Cycle, in press.
  • Zuo Y, Berdeaux R and Frost JA. (2014).  The RhoGEF Net1 is required for normal mammary gland development. Mol Endo, 28(12):1948-60.
  • Zuo Y, Oh W and Frost JA. (2014).  Controlling the switches: Rho GTPase regulation during animal cell mitosis. Cell Signaling, 26(12):2998-3006.
  • Carr HS, Zuo Y, Oh W, and Frost JA. (2013).  The RhoA GEF Net1 controls FAK activation to regulate breast cancer cell migration and invasion. Mol Cell Biol, 33(14), 2773-2786.
  • Menon S, and Frost JA. (2013).  The RhoA GEF Net1 controls mitotic Pak and Aurora A activation to regulate mitotic progression. Mol Biol Cell, 24(17), 2655-2657.
  • Carr HS, and Frost JA. (2013).  Timing is everything: Rac1 controls Net1A localization to regulate cell adhesion. Cell Adhes Migrat, 7(4), 351-356.
  • Carr HS, Morris CA, Menon S, Song EH, Frost JA. (2012).  Rac1 controls the subcellular localization of the RhoGEF Net1A to regulated focal adhesion formation and cell spreading. Mol Cell Biol, 33(3), 622-634.
  • Frost JA. (2011).  Net1. (Neuroepithelial Cell Transforming Gene 1 Protein). Encyclopedia of Signaling Molecules. In: Choi S. (eds) Encyclopedia of Signaling Molecules. Springer, Cham.
  • Pichot CS, Hartig SM, Arvanitis D, Jensen S, Bechill J, Marzouk S, Scita G, Frost JA, and Corey SJ. (2010).  Cdc42 Interacting Protein 4 promotes breast cancer cell invasion and formation of invadopodia through activation of N-WASP. Cancer Res 70, 8347-8356.
  • Ross JA, Hanyin CH, Nagy ZS, Frost JA, and Kirken RA. (2010).  Protein Phosphatase 2A (PP2A) regulates Interleukin-2 Receptor complex formation and JAK3/STAT5 activation, J Biol Chem 285, 3582-3591.
  • Carr HS, Cai C, Keinanen K, and Frost JA. (2009). Interaction of the RhoA exchange factor Net1 with Dlg1 protects it from proteasome mediated degradation and potentiates Net1 activity. J Biol Chem, 284, 24269-24280.
  • Gilcrease MZ, Kilpatrick SK, Woodward WA, Zhou X, Nicolas MM, Corley LJ, Fuller GN, Tucker SL, Diaz LK, Buchholz TA, and Frost JA. (2009).  Co- Expression of Beta4 Integrin and Guanine Nucleotide Exchange Factor Net1 Identifies an Aggressive Subgroup of HER2-Positive Breast Cancer. Cancer Epidemiology, Biomarkers and Prevention, 18, 80-86.
  • Pichot CS, Hartig M, Xia L, Lee FY, Frost JA, and Corey SJ. (2009).  Dasatinib Synergizes with Doxorubicin to Block Growth, Migration, and Invasion of Breast Cancer Cells. British J Cancer, 101, 38-47.
  • Frost JA. (2008).  Net1. UCSD-Nature Molecule Pages (doi:10.1038/mp.a001630.01)
  • Garcia-Mata R, Dubash A, Sharek L, Carr HS, Frost JA, and Burridge K. (2007). The nuclear RhoA exchange factor NET1 interacts with proteins of the DLG family, affects their localization and influences their tumor suppressive activity. Mol Cell Biol 27(24), 8683-8697.
  • Wu X, and Frost JA. (2006).  Multiple Rho Proteins Regulate the Subcellular Targeting of PAK5. Biochem and Biophys Res Com 351(2), 328-335.
  • Qin H, Carr HS, Wu X, Muallem D, Tran DH, and Frost JA. (2005). Characterization of the Biochemical and Transforming Properties of the Neuroepithelioma Transforming Gene 1. J Biol Chem  280 (9), 7603-7613.
  • Albert AS, Qin H, Carr HS, and Frost JA. (2005). PAK 1 Negatively Regulates the Activity of the Rho Exchange Factor Net 1. J Biol Chem 280 (13),12152-12161.
  • Tran NH, Wu X, and Frost JA. (2005).  B-Raf and Raf-1 are Regulated by Distinct Auto regulatory Mechanisms. J Biol Chem 280 (16), 16244-16253
  • Tran N, and Frost JA.  (2003).  Phosphorylation of Raf-1 by PAK1 and Src Regulates Raf-1 Auto inhibition. J Biol Chem, 11221-11226.
  • Cobb, MH, Xu S, Hepler JE, Hutchison M, Frost J and Robbins DR. (1994). Regulation of the MAP kinase cascade. Cell and Mol Biol Res, 40(3), 253-256.